Fluoride-Free Anticavity Oral Care Compositions

ABSTRACT

Fluoride-free oral care compositions with an anticaries or anticavity effect. Oral care compositions that are fluoride-free and have an extract from a species in the Humulus family. Oral care compositions that are fluoride-free and have an extract from  Humulus lupulus . Oral care compositions that are fluoride-free and have a hops beta acid.

FIELD OF THE INVENTION

The present invention is directed to compositions with anticariesactivity. The present invention is also directed to fluoride-freecompositions with anticaries activity. The present invention is alsodirected to fluoride-free compositions comprising hops beta acid, suchas from an extract from Humulus lupulus.

BACKGROUND OF THE INVENTION

Oral care compositions, such as toothpaste and/or dentifricecompositions, can be applied to the oral cavity to clean and/or maintainthe aesthetics and/or health of the teeth, gums, and/or tongue.Additionally, many oral care compositions are used to deliver activeingredients directly to oral care surfaces. For example, toothpastecompositions can have fluoride, from such as sodium fluoride, sodiummonofluorophosphate, and/or stannous fluoride, as an anticaries drug.While the effectiveness and safety of fluoride as an anticaries drug iswell established, many consumers desire a fluoride-free oral carecomposition.

However, current fluoride-free oral care compositions do not provideenough, or any, protection from caries due to the acids produced bybacteria found on the surfaces of teeth. As such, there is a need fororal care compositions that are both fluoride-free and provide ananticavity benefit.

SUMMARY OF THE INVENTION

Disclosed herein is an oral care composition comprising (a) from about0.01% to about 10%, by weight of the composition, of hops beta acid; and(b) abrasive, wherein the oral care composition is free of fluoride.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of hops betaacid; and (b) from about 10% to about 50%, by weight of the composition,of calcium, wherein the oral care composition is free of silica.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of antibacterialagent; and (b) from about 10% to about 50%, by weight of thecomposition, of calcium, wherein the oral care composition is free of asilica abrasive and has a percent glycolysis inhibition of at least 60%in the in vitro Plaque Glycolysis and Regrowth Model.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of hops betaacid; (b) from about 0.01% to about 10%, by weight of the composition,of a metal ion source; (c) from about 10% to about 50%, by weight of thecomposition, of calcium; and (d) from about 1% to about 20%, by weightof the composition, of buffering agent, wherein the oral carecomposition is free of fluoride.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of lupulone; (b)from about 0.01% to about 10%, by weight of the composition, of tin; (c)from about 10% to about 50%, by weight of the composition, of calciumcarbonate; and (d) from about 1% to about 20%, by weight of thecomposition, of buffering agent, wherein the oral care composition isfree of fluoride.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of hops betaacid; (b) from about 0.01% to about 10%, by weight of the composition,of stannous chloride; (c) from about 10% to about 50%, by weight of thecomposition, of calcium carbonate; and (d) from about 1% to about 20%,by weight of the composition, of buffering agent, wherein the oral carecomposition is free of fluoride.

Also disclosed herein is a method of preventing caries comprising (a)providing a fluoride-free toothpaste composition comprising one or morehops beta acids; and (b) applying the fluoride-free toothpastecomposition to the oral cavity.

Also disclosed herein is an oral care composition comprising (a) fromabout 0.01% to about 10%, by weight of the composition, of hops betaacid; and (b) from about 0.01% to about 10%, by weight of thecomposition, of sweetener.

Also disclosed herein is a method of preventing caries comprising (a)providing any one of the oral care compositions as disclosed herein, and(b) applying the selected oral care composition to the oral cavity.

Also disclosed is an oral care composition comprising: (a) from about0.01% to about 10%, by weight of the composition, of hops beta acid; and(b) from about 0.01% to about 10%, by weight of the composition, ofantibacterial agent, wherein the oral care composition is free offluoride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to oral care compositions that arefluoride-free, yet still provide an anticavity and/or anticariesbenefit. Dental caries, or tooth decay, is a breakdown of the teeth dueto the acids made by bacteria. Cavities are caused by the acid producedby bacteria dissolving the hard tissues of the teeth, such as enamel,dentin, and/or cementum. The acid is produced by the bacteria when thebacteria breaks down food debris or sugar on the tooth's surface.

Fluoride works by making the tooth's surface less soluble to the acidproduced by the bacteria, “plaque acid.” Tooth's enamel is made fromhydroxyapatite (Ca₅(PO₄)₃(OH)). Hydroxyapatite can be dissolved from theenamel at a pH of under 5.5 (demineralization). If hydroxyapatite isdemineralized in the presence of fluoride ions, fluorapatite(Ca₅(PO₄)₃(F)) can remineralize on the surface of a tooth's enamel. Insum, this process is a replacement of a hydroxyl (OH) ion with afluoride (F) ion. Fluorapatite is inherently less soluble thanhydroxyapatite, even under acidic conditions. Thus, fluoride works as ananticaries drug to make the tooth's surface more resistant and lesssoluble to plaque acid.

While not wishing to being bound by theory, it is believed that thedisclosed oral care compositions have a different mechanism of actionthan fluoride ion therapy. In contrast to the single symptom treatmentof fluoride (i.e. treating the result of plaque acid), the disclosedcompositions are believed to have anticavity activity through acombination of effects that collectively lead to an anticavity effect.While not wishing to being bound by theory, it is believed that thedisclosed oral care compositions have an anticavity effect by providingone or more of the following outcomes: (1) suppressing plaque acidproduction, (2) neutralizing plaque acids that are produced, and/or (3)reducing the solubility of the hydroxyapatite hard tissue surface.

The suppression of plaque acid production can be accomplished byproviding one or more antibacterial agents to kill the source of theplaque acid (i.e. the bacteria itself) and/or providing one or morebiofilm modifiers to disrupt and embed antibacterial agents within thebiofilm matrix.

Neutralizing the plaque acids can be accomplished by providing one ormore biofilm modifiers to disrupt the biofilm matrix and/or providingone or more buffering agents to buffer the produced plaque acid and/orincreasing the saturation of calcium ions on the enamel surface byproviding one or more calcium ion sources.

Reducing the solubility of the hydroxyapatite hard tissue surface can beaccomplished by providing one or more calcium ion sources. This cancreate a supersaturated environment of calcium and/or phosphate ionsaround the hydroxyapatite surface, which can shift the equilibrium ofFormula I in favor of remineralization of hydroxyapatite according to LeChatelier's principle.

Ca₁₀(PO₄)₆(OH)₂⇄10Ca²⁺+6PO₄ ³⁻  Formula I. Hydroxyapatite

Reducing the solubility of the hydroxyapatite hard tissue surface canalso be accomplished by surface adsorbing metal ions that slow thedissolution of the enamel by forming an acid resistant surface layer.This may be accomplished, for example, by depositing stannous ions onthe surface of enamel.

While each of these mechanisms might not be enough, on its own, toprovide an anticavity benefit equivalent to a therapeutic dose offluoride, in combination these mechanisms can provide an anticavitybenefit. As such, the present invention is directed to compositions andmethods of use of the compositions that are fluoride-free, yet stillprovide an anticavity and/or anticaries benefit.

Definitions

To define more clearly the terms used herein, the following definitionsare provided. Unless otherwise indicated, the following definitions areapplicable to this disclosure. If a term is used in this disclosure butis not specifically defined herein, the definition from the IUPACCompendium of Chemical Terminology, 2nd Ed (1997), can be applied, aslong as that definition does not conflict with any other disclosure ordefinition applied herein, or render indefinite or non-enabled any claimto which that definition is applied.

The term “oral care composition”, as used herein, includes a product,which in the ordinary course of usage, is not intentionally swallowedfor purposes of systemic administration of particular therapeuticagents, but is rather retained in the oral cavity for a time sufficientto contact dental surfaces or oral tissues. Examples of oral carecompositions include dentifrice, toothpaste, tooth gel, subgingival gel,mouth rinse, mousse, foam, mouth spray, lozenge, chewable tablet,chewing gum, tooth whitening strips, floss and floss coatings, breathfreshening dissolvable strips, or denture care or adhesive product. Theoral care composition may also be incorporated onto strips or films fordirect application or attachment to oral surfaces.

“Active and other ingredients” useful herein may be categorized ordescribed herein by their cosmetic and/or therapeutic benefit or theirpostulated mode of action or function. However, it is to be understoodthat the active and other ingredients useful herein can, in someinstances, provide more than one cosmetic and/or therapeutic benefit orfunction or operate via more than one mode of action. Therefore,classifications herein are made for the sake of convenience and are notintended to limit an ingredient to the particularly stated function(s)or activities listed.

The term “orally acceptable carrier” comprises one or more compatiblesolid or liquid excipients or diluents which are suitable for topicaloral administration. By “compatible,” as used herein, is meant that thecomponents of the composition are capable of being commingled withoutinteraction in a manner which would substantially reduce thecomposition's stability and/or efficacy.

The term “substantially free” as used herein refers to the presence ofno more than 0.05%, preferably no more than 0.01%, and more preferablyno more than 0.001%, of an indicated material in a composition, by totalweight of such composition.

The term “essentially free” as used herein means that the indicatedmaterial is not deliberately added to the composition, or preferably notpresent at analytically detectable levels. It is meant to includecompositions whereby the indicated material is present only as animpurity of one of the other materials deliberately added.

While compositions and methods are described herein in terms of“comprising” various components or steps, the compositions and methodscan also “consist essentially of” or “consist of” the various componentsor steps, unless stated otherwise.

As used herein, the word “or” when used as a connector of two or moreelements is meant to include the elements individually and incombination; for example, X or Y, means X or Y or both.

As used herein, the articles “a” and “an” are understood to mean one ormore of the material that is claimed or described, for example, “an oralcare composition” or “a bleaching agent.”

All measurements referred to herein are made at about 23° C. (i.e. roomtemperature) unless otherwise specified.

Generally, groups of elements are indicated using the numbering schemeindicated in the version of the periodic table of elements published inChemical and Engineering News, 63(5), 27, 1985. In some instances, agroup of elements can be indicated using a common name assigned to thegroup; for example, alkali metals for Group 1 elements, alkaline earthmetals for Group 2 elements, and so forth.

Several types of ranges are disclosed in the present invention. When arange of any type is disclosed or claimed, the intent is to disclose orclaim individually each possible number that such a range couldreasonably encompass, including end points of the range as well as anysub-ranges and combinations of sub-ranges encompassed therein.

The term “about” means that amounts, sizes, formulations, parameters,and other quantities and characteristics are not and need not be exact,but can be approximate and/or larger or smaller, as desired, reflectingtolerances, conversion factors, rounding off, measurement errors, andthe like, and other factors known to those of skill in the art. Ingeneral, an amount, size, formulation, parameter or other quantity orcharacteristic is “about” or “approximate” whether or not expresslystated to be such. The term “about” also encompasses amounts that differdue to different equilibrium conditions for a composition resulting froma particular initial mixture. Whether or not modified by the term“about,” the claims include equivalents to the quantities. The term“about” can mean within 10% of the reported numerical value, preferablywithin 5% of the reported numerical value.

The oral care composition can be in any suitable form, such as a solid,liquid, powder, paste, or combinations thereof. The oral carecomposition can be dentifrice, tooth gel, subgingival gel, mouth rinse,mousse, foam, mouth spray, lozenge, chewable tablet, chewing gum, toothwhitening strips, floss and floss coatings, breath fresheningdissolvable strips, or denture care or adhesive product. The componentsof the dentifrice composition can be incorporated into a film, a strip,a foam, or a fiber-based dentifrice composition. The oral carecomposition can include a variety of active and inactive ingredients,such as, for example, but not limited to a hops extract, a tin ionsource, a calcium ion source, water, a fluoride ion source, zinc ionsource, one or more polyphosphates, humectants, surfactants, otheringredients, and the like, as well as any combination thereof, asdescribed below.

Section headers are provided below for organization and convenienceonly. The section headers do not suggest that a compound cannot bewithin more than one section. In fact, compounds can fall within morethan one section. For example, stannous chloride can be both a tin ionsource and a biofilm modifier, stannous fluoride can be both a tin ionsource and a fluoride ion source, glycine can be an amino acid, abuffering agent, and/or a biofilm modifier, among numerous othercompounds that can fit amongst several categories and/or sections.

Humulus lupulus

The oral care compositions of the present invention comprise at leastone hops compound from Formula I and/or Formula IV. The compound fromFormula I and/or Formula IV can be provided by any suitable source, suchas an extract from Humulus lupulus or Hops, Humulus lupulus itself, asynthetically derived compound, and/or salts, prodrugs, or other analogsthereof. The hops extract can comprise one or more hops alpha acids, oneor more hops iso-alpha acids, one or more hops beta acids, one or morehops oils, one or more flavonoids, one or more solvents, and/or water.Suitable hops alpha acids (generically shown in Formula I) can includehumulone (Formula II), adhumulone, cohumulone, posthumulone,prehumulone, and/or mixtures thereof. Suitable hops iso-alpha acids caninclude cis-isohumulone and/or trans-isohumulone. The isomerization ofhumulone into cis-isohumulone and trans-isohumulone can be representedby Formula III.

A is the acidic hydroxyl functional group in the alpha position, B arethe acidic hydroxyl functional groups in the beta position, and R is analkyl functional group.

Suitable hops beta acids can include lupulone, adlupulone, colupulone,and/or mixtures thereof. A suitable hops beta acid can include acompound a described in Formula IV, V, VI, and/or VII.

B are the acidic hydroxyl functional groups in the beta position and Ris an alkyl functional group.

While hops alpha acids can demonstrate some antibacterial activity, hopsalpha acids also have a bitter taste. The bitterness provided by hopsalpha acids can be suitable for beer, but are not suitable for use inoral care compositions. In contrast, hops beta acids can be associatedwith a higher antibacterial and/or anticaries activity, but not asbitter a taste. Thus, a hops extract with a higher proportion of betaacids to alpha acids than normally found in nature, can be suitable foruse in oral care compositions for use as an antibacterial and/oranticaries agent.

A natural hops source can comprise from about 2% to about 12%, by weightof the hops source, of hops beta acids depending on the variety of hops.Hops extracts used in other contexts, such as in the brewing of beer,can comprise from about 15% to about 35%, by weight of the extract, ofhops beta acids. The hops extract desired herein can comprise at leastabout 35%, at least about 40%, at least about 45%, from about 35% toabout 95%, from about 40% to about 90%, or from about 45% to about 99%,of hops beta acids. The hops beta acids can be in an acidic form (i.e.with attached hydrogen atom(s) to the hydroxl functional group(s)) or asa salt form.

A suitable hops extract is described in detail in U.S. Pat. No.7,910,140, which is herein incorporated by reference in its entirety.The hops beta acids desired can be non-hydrogenated, partiallyhydrogenated by a non-naturally occurring chemical reaction, orhydrogenated by a non-naturally occurring chemical reaction. The hopsbeta acid can be essentially free of or substantially free ofhydrogenated hops beta acid and/or hops acid. A non-naturally occurringchemical reaction is a chemical reaction that was conducted with the aidof chemical compound not found within Humulus lupulus, such as achemical hydrogenation reaction conducted with high heat not normallyexperienced by Humulus lupulus in the wild and/or a metal catalyst.

A natural hops source can comprise from about 2% to about 12%, by weightof the hops source, of hops alpha acids. Hops extracts used in othercontexts, such as in the brewing of beer, can comprise from about 15% toabout 35%, by weight of the extract, of hops alpha acids. The hopsextract desired herein can comprise less than about 10%, less than about5%, less than about 1%, or less than about 0.5%, by weight of theextract, of hops alpha acids.

Hops oils can include terpene hydrocarbons, such as myrcene, humulene,caryophyllene, and/or mixtures thereof. The hops extract desired hereincan comprise less than 5%, less than 2.5%, or less than 2%, by weight ofthe extract, of one or more hops oils. Flavonoids present in the hopsextract can include xanthohumol, 8-prenylnaringenin, isoxanthohumol,and/or mixtures thereof. The hops extract can be substantially free of,essentially free of, free of, or have less than 250 ppm, less than 150ppm, and/or less than 100 ppm of one or more flavonoids.

As described in U.S. Pat. No. 5,370,863, hops acids have been previouslyadded to oral care compositions. However, the oral care compositionstaught by U.S. Pat. No. 5,370,863 only included up to 0.01%, by weightof the oral care composition. While not wishing to be bound by theory,it is believed that U.S. Pat. No. 5,370,863 could only incorporate a lowamount of hops acids because of the bitterness of hops alpha acids. Ahops extract with a low level of hops alpha acids would not have thisconcern.

The hops compound can be combined with or free from an extract fromanother plant, such as a species from genus Magnolia. The hops compoundscan be combined with or free from triclosan.

The oral care composition can comprise from about 0.01% to about 10%,greater than 0.01% to about 10%, from about 0.05%, to about 10%, fromabout 0.1% to about 10%, from about 0.2% to about 10%, from about 0.2%to about 10%, from about 0.2% to about 5%, from about 0.25% to about 2%,from about 0.05% to about 2%, or from greater than 0.25% to about 2%, ofhops beta acid, as described herein. The hops beta acids can be providedby a suitable hops extract, the hops plant itself, or a syntheticallyderived compound. The hops beta acid can be provided as neutral, acidiccompounds, and/or as salts with a suitable counter ion, such as sodium,potassium, ammonia, or any other suitable counter ion.

The hops beta acid can be provided by a hops extract, such as an extractfrom Humulus lupulus with at least 35%, by weight of the extract, ofhops beta acid and less than 1%, by weight of the hops extract, of hopsalpha acid. The oral care composition can comprise 0.01% to about 10%,greater than 0.01% to about 10%, from about 0.05%, to about 10%, fromabout 0.1% to about 10%, from about 0.2% to about 10%, from about 0.2%to about 10%, from about 0.2% to about 5%, from about 0.25% to about 2%,from about 0.05% to about 2%, or from greater than 0.25% to about 2%, ofhops extract, as described herein.

Fluoride Ion Source

The oral care composition can comprise fluoride, such as from a fluorideion source. The fluoride ion source can comprise one or more fluoridecontaining compounds, such as stannous fluoride, sodium fluoride,titanium fluoride, calcium fluoride, calcium phosphate silicatefluoride, potassium fluoride, amine fluoride, sodiummonofluorophosphate, zinc fluoride, and/or mixtures thereof.

The fluoride ion source and the tin ion source can be the same compound,such as for example, stannous fluoride, which can generate tin ions andfluoride ions. Additionally, the fluoride ion source and the tin ionsource can be separate compounds, such as when the tin ion source isstannous chloride and the fluoride ion source is sodiummonofluorophosphate or sodium fluoride.

The fluoride ion source and the zinc ion source can be the samecompound, such as for example, zinc fluoride, which can generate zincions and fluoride ions. Additionally, the fluoride ion source and thezinc ion source can be separate compounds, such as when the zinc ionsource is zinc phosphate and the fluoride ion source is stannousfluoride.

The fluoride ion source can be essentially free of or free of stannousfluoride. Thus, the oral care composition can comprise sodium fluoride,potassium fluoride, amine fluoride, sodium monofluorophosphate, zincfluoride, and/or mixtures thereof.

The oral care composition can comprise a fluoride ion source capable ofproviding from about 50 ppm to about 5000 ppm, and preferably from about500 ppm to about 3000 ppm of free fluoride ions. To deliver the desiredamount of fluoride ions, the fluoride ion source may be present in theoral care composition at an amount of from about 0.0025% to about 5%,from about 0.01% to about 10%, from about 0.2% to about 1%, from about0.5% to about 1.5%, or from about 0.3% to about 0.6%, by weight of theoral care composition. Alternatively, the oral care composition cancomprise less than 0.1%, less than 0.01%, be essentially free of,substantially free of, or free of a fluoride ion source.

Tin Ion Source

The oral care composition of the present invention can comprise tin,such as from a tin ion source. The tin ion source can be any suitablecompound that can provide tin ions in an oral care composition and/ordeliver tin ions to the oral cavity when the dentifrice composition isapplied to the oral cavity. The tin ion source can comprise one or moretin containing compounds, such as stannous fluoride, stannous chloride,stannous bromide, stannous iodide, stannous oxide, stannous oxalate,stannous sulfate, stannous sulfide, stannic fluoride, stannic chloride,stannic bromide, stannic iodide, stannic sulfide, and/or mixturesthereof. Tin ion source can comprise stannous fluoride, stannouschloride, and/or mixture thereof. The tin ion source can also be afluoride-free tin ion source, such as stannous chloride.

The oral care composition can comprise from about 0.0025% to about 5%,from about 0.01% to about 10%, from about 0.2% to about 1%, from about0.5% to about 1.5%, or from about 0.3% to about 0.6%, by weight of theoral care composition, of a tin ion source.

Ca Ion Source

The oral care composition of the present invention can comprise calcium,such as from a calcium ion source. The calcium ion source can be anysuitable compound or molecule that can provide calcium ions in an oralcare composition and/or deliver calcium ions to the oral cavity when theoral care composition is applied to the oral cavity. The calcium ionsource can comprise a calcium salt, a calcium abrasive, and/orcombinations thereof. In some cases, a calcium salt may also beconsidered a calcium abrasive or a calcium abrasive may also beconsidered a calcium salt.

The calcium ion source can comprise a calcium abrasive. The calciumabrasive can be any suitable abrasive compound that can provide calciumions in an oral care composition and/or deliver calcium ions to the oralcavity when the oral care composition is applied to the oral cavity. Thecalcium abrasive can comprise one or more calcium abrasive compounds,such as calcium carbonate, precipitated calcium carbonate (PCC), groundcalcium carbonate (GCC), chalk, dicalcium phosphate, calciumpyrophosphate, and/or mixtures thereof.

The calcium ion source can comprise a calcium salt, or a compound thatcan provide calcium ions in an oral care composition and/or delivercalcium ions to the oral cavity when the oral care composition isapplied to the oral cavity that can not act as an abrasive. The calciumsalt can comprise one or more calcium compounds, such as calciumchloride, calcium nitrate, calcium phosphate, calcium lactate, calciumoxalate, calcium oxide, calcium gluconate, calcium citrate, calciumbromide, calcium iodate, calcium iodide, hydroxyapatite, fluorapatite,calcium sulfate, calcium glycerophosphate, and/or combinations thereof.

The oral care composition can comprise from about 5% to about 70%, fromabout 10% to about 50%, from about 10% to about 60%, from about 20% toabout 50%, from about 25% to about 40%, or from about 1% to about 50% ofa calcium ion source.

Buffering Agent

The oral care composition can comprise a buffering agent. The bufferingagent can be a weak acid or base that can maintain a particular pH at aselected site in the oral cavity. For example, the buffering agent canmaintain a pH at a tooth's surface to mitigate the impact of plaqueacids produced by bacteria. The buffering agent can comprise a conjugateacid of an ion also present in the oral care composition. For example,if the calcium ion source comprises calcium carbonate, the bufferingagent can comprise a bicarbonate anion (—HCO₃ ⁻). The buffering agentcan comprise a conjugate acid/base pair, such as citric acid and sodiumcitrate.

Suitable buffering systems can include phosphate, citrate salts,carbonate/bicarbonate salts, a tris buffer, imidazole, urea, borate,and/or combinations thereof. Suitable buffering agents includebicarbonate salts, such as sodium bicarbonate, glycine, orthophosphate,arginine, urea, and or/combinations thereof.

The oral care composition can comprise from about 1% to about 30%, fromabout 5% to about 25% or from about 10% to about 20%, of one or morebuffering agents.

Biofilm Modifier

The oral care composition can comprise one or more biofilm modifiers. Abiofilm modifier can comprise a polyol, an ammonia generating compound,and/or a glucosyltransferase inhibitor.

A polyol is an organic compound with more than one hydroxyl functionalgroups. The polyol can be any suitable compound that can weaklyassociate, interact, or bond to tin ions while the oral care compositionis stored prior to use. The polyol can be a sugar alcohol, which areaclass of polyols that can be obtained through the hydrogenation of sugarcompounds with the formula (CHOH)_(n)H₂. The polyol can be glycerin,erythritol, xylitol, sorbitol, mannitol, butylene glycol, lactitol,and/or combinations thereof. The oral care composition can comprise0.01% to about 70%, from about 5% to about 70%, from about 5% to about50%, from about 10% to about 60%, from about 10% to about 25%, or fromabout 20% to about 80%, by weight of the oral care composition, of apolyol.

The ammonia generating compound can be any suitable compound that cangenerate ammonia upon delivery to the oral cavity. Suitable ammoniagenerating compounds include arginine, urea, and/or combinationsthereof. The oral care composition can comprise from about 0.01% toabout 10%, from about 1% to about 5%, or from about 1% to about 25% ofone or more ammonia generating compounds.

The glucosyltransferase inhibitor can be any suitable compound that caninhibit a glucosyltransferase. Glucosyltransferases are enzymes that canestablish natural glycosidic linkages. In particular, these enzymesbreak down poly- or oligosaccharide moieties into simple sugars forbacteria associated with dental caries. As such, any compound that caninhibit this process can help prevent dental caries. Suitableglucosyltransferase inhibitors include oleic acid, epicatechin, tannins,tannic acid, moenomycin, caspofungin, ethambutol, lufenuron, and/orcombinations thereof. The oral care composition can comprise from about0.001% to about 5%, from about 0.01% to about 2%, or about 1% of one ormore glucosyltransferase inhibitors.

Metal Ion Source

The oral care composition can comprise metal, such as from a metal ionsource comprising one or more metal ions. The metal ion source cancomprise or be in addition to the tin ion source and/or the zinc ionsource, as described herein. Suitable metal ion sources includecompounds with metal ions, such as, but not limited to Sn, Zn, Cu, Mn,Mg, Sr, Ti, Fe, Mo, B, Ba, Ce, Al, In and/or mixtures thereof. The tracemetal source can be any compound with a suitable metal and anyaccompanying ligands and/or anions.

Suitable ligands and/or anions that can be paired with metal ion sourcesinclude, but are not limited to acetate, ammonium sulfate, benzoate,bromide, borate, carbonate, chloride, citrate, gluconate,glycerophosphate, hydroxide, iodide, oxide, propionate, D-lactate,DL-lactate, orthophosphate, pyrophosphate, sulfate, nitrate, tartrate,and/or mixtures thereof.

The oral care composition can comprise from about 0.01% to about 10%,from about 1% to about 5%, or from about 0.5% to about 15% of a metalion source.

Antibacterial Agents

The oral care composition can comprise one or more antibacterial agents.Suitable antibacterial agents include any molecule that providesantibacterial activity in the oral cavity. Suitable antibacterial agentsinclude hops acids, tin ion sources, benzyl alcohol, sodium benzoate,menthylglycyl acetate, menthyl lactate, L-menthol, o-neomenthol,chlorophyllin copper complex, phenol, oxyquinoline, and/or combinationsthereof.

The oral care composition can comprise from about 0.01% to about 10%,from about 1% to about 5%, or from about 0.5% to about 15% of anantibacterial agent.

Bioactive Materials

The oral care composition can also include bioactive materials suitablefor the remineralization of a tooth. Suitable bioactive materialsinclude bioactive glasses, Novamin™, Recaldent™, hydroxyapatite, one ormore amino acids, such as, for example, arginine, citrulline, glycine,lysine, or histidine, or combinations thereof. Suitable examples ofcompositions comprising arginine are found in U.S. Pat. No. 4,154,813and 5,762,911, which are herein incorporated by reference in theirentirety. Other suitable bioactive materials include any calciumphosphate compound. Other suitable bioactive materials include compoundscomprising a calcium source and a phosphate source.

Amino acids are organic compounds that contain an amine functionalgroup, a carboxyl functional group, and a side chain specific to eachamino acid. Suitable amino acids include, for example, amino acids witha positive or negative side chain, amino acids with an acidic or basicside chain, amino acids with polar uncharged side chains, amino acidswith hydrophobic side chains, and/or combinations thereof. Suitableamino acids also include, for example, arginine, histidine, lysine,aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine,cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine,leucine, methionine, phenylalanine, tyrosine, tryptophan, citrulline,ornithine, creatine, diaminobutonic acid, diaminoproprionic acid, saltsthereof, and/or combinations thereof.

Bioactive glasses are comprising calcium and/or phosphate which can bepresent in a proportion that is similar to hydroxyapatite. These glassescan bond to the tissue and are biocompatible. Bioactive glasses caninclude a phosphopeptide, a calcium source, phosphate source, a silicasource, a sodium source, and/or combinations thereof.

The oral care composition can comprise from about 0.01% to about 20%,from about 0.1% to about 10%, or from about 1% to about 10% of abioactive material by weight of the oral care composition.

Abrasive

The oral care composition can comprise a calcium abrasive, as describedherein, and/or a non-calcium abrasive, such as bentonite, silica gel (byitself, and of any structure), precipitated silica, amorphousprecipitated silica (by itself, and of any structure as well), hydratedsilica, perlite, titanium dioxide, calcium pyrophosphate, dicalciumphosphate dihydrate, alumina, hydrated alumina, calcined alumina,aluminum silicate, insoluble sodium metaphosphate, insoluble potassiummetaphosphate, insoluble magnesium carbonate, zirconium silicate,particulate thermosetting resins and other suitable abrasive materials.Such materials can be introduced into the oral care compositions totailor the polishing characteristics of the target dentifriceformulation. The oral care composition can comprise from about 5% toabout 70%, from about 10% to about 50%, from about 10% to about 60%,from about 20% to about 50%, from about 25% to about 40%, or from about1% to about 50%, by weight of the oral care composition, of thenon-calcium abrasive.

Alternatively, the oral care composition can be substantially free of,essentially free of, or free of silica, alumina, or any othernon-calcium abrasive. The oral care composition can comprise less thanabout 5%, less than about 1%, less than about 0.5%, less than about0.1%, or 0% of a non-calcium abrasive, such as silica and/or alumina.

Water

The oral care composition of the present invention can be anhydrous, alow water formulation, or a high water formulation. In total, the oralcare composition can comprise from 0% to about 99%, from about 5% toabout 75%, about 20% or greater, about 30% or greater, or about 50% orgreater by weight of the composition, of water. Preferably, the water isUSP water.

In a high water oral care composition and/or toothpaste formulation, theoral care composition comprises from about 45% to about 75%, by weightof the composition, of water. The high water oral care compositionand/or toothpaste formulation can comprise from about 45% to about 65%,from about 45% to about 55%, or from about 46% to about 54%, by weightof the composition, of water. The water may be added to the high waterformulation and/or may come into the composition from the inclusion ofother ingredients.

In a low water oral care composition and/or toothpaste formulation, theoral care composition comprises from about 5% to about 45%, by weight ofthe composition, of water. The low water oral care composition cancomprise from about 5% to about 35%, from about 10% to about 25%, orfrom about 20% to about 25%, by weight of the composition, of water. Thewater may be added to the low water formulation and/or may come into thecomposition from the inclusion of other ingredients.

In an anhydrous oral care composition and/or toothpaste formulation, theoral care composition comprises less than about 10%, by weight of thecomposition, of water. The anhydrous composition comprises less thanabout 5%, less than about 1%, or 0%, by weight of the composition, ofwater. The water may be added to the anhydrous formulation and/or maycome into the composition from the inclusion of other ingredients.

A mouth rinse formulation comprises from about 75% to about 99%, fromabout 75% to about 95%, or from about 80% to about 95% of water.

The composition can also comprise other orally acceptable carriermaterials, such as alcohol, humectants, polymers, surfactants, andacceptance improving agents, such as flavoring, sweetening, coloringand/or cooling agents.

pH

The pH of the disclosed composition can be from about 4 to about 10,from about 7 to about 10, greater than 7 to about 10, greater than 8 toabout 10, greater than 7, greater than 7.5, greater than 8, greater than9, or from about 8.5 to about 10.

Zinc Ion Source

The oral care composition can comprise zinc, such as from a zinc ionsource. The zinc ion source can comprise one or more zinc containingcompounds, such as zinc fluoride, zinc lactate, zinc oxide, zincphosphate, zinc chloride, zinc acetate, zinc hexafluorozirconate, zincsulfate, zinc tartrate, zinc gluconate, zinc citrate, zinc malate, zincglycinate, zinc pyrophosphate, zinc metaphosphate, zinc oxalate, and/orzinc carbonate. The zinc ion source can be a fluoride-free zinc ionsource, such as zinc phosphate, zinc oxide, and/or zinc citrate.

The zinc ion source may be present in the total oral care composition atan amount of from about 0.01% to about 10%, from about 0.2% to about 1%,from about 0.5% to about 1.5%, or from about 0.3% to about 0.6%, byweight of the dentifrice composition.

Polyphosphates

The oral care composition can comprise polyphosphate, such as from apolyphosphate source. A polyphosphate source can comprise one or morepolyphosphate molecules. Polyphosphates are a class of materialsobtained by the dehydration and condensation of orthophosphate to yieldlinear and cyclic polyphosphates of varying chain lengths. Thus,polyphosphate molecules are generally identified with an average number(n) of polyphosphate molecules, as described below. A polyphosphate isgenerally understood to consist of two or more phosphate moleculesarranged primarily in a linear configuration, although some cyclicderivatives may be present.

Preferred polyphosphates are those having an average of two or morephosphate groups so that surface adsorption at effective concentrationsproduces sufficient non-bound phosphate functions, which enhance theanionic surface charge as well as hydrophilic character of the surfaces.Preferred in this invention are the linear polyphosphates having theformula: XO(XPO₃)_(n)X, wherein X is sodium, potassium, ammonium, or anyother alkali metal cations and n averages from about 2 to about 21.Alkali earth metal cations, such as calcium, are not preferred becausethey tend to form insoluble fluoride salts from aqueous solutionscomprising a fluoride ions and alkali earth metal cations. Thus, theoral care compositions disclosed herein can be free of, essentially freeof, or substantially free of calcium pyrophosphate.

Some examples of suitable polyphosphate molecules include, for example,pyrophosphate (n=2), tripolyphosphate (n=3), tetrapoiyphosphate (n=4),sodaphos polyphosphate (n=6), hexaphos polyphosphate (n=13), benephospolyphosphate (n=14), hexametaphosphate (n=21), which is also known asGlass H. Polyphosphates can include those polyphosphate compoundsmanufactured by FMC Corporation, ICL Performance Products, and/orAstaris.

The oral care composition can comprise from about 0.01% to about 15%,from about 0.1% to about 10%, from about 0.5% to about 5%, from about 1to about 20%, or about 10% or less, by weight of the oral carecomposition, of the polyphosphate source.

Humectants

The oral care composition can comprise one or more humectants, have lowlevels of a humectant, be essentially free of, be substantially free of,or be free of a humectant. Humectants serve to add body or “mouthtexture” to an oral care composition or dentifrice as well as preventingthe dentifrice from drying out. Suitable humectants include polyethyleneglycol (at a variety of different molecular weights), propylene glycol,glycerin (glycerol), erythritol, xylitol, sorbitol, mannitol, butyleneglycol, lactitol, hydrogenated starch hydrolysates, and/or mixturesthereof. The oral care composition can comprise one or more humectantseach at a level of from 0 to about 70%, from about 5% to about 50%, fromabout 10% to about 60%, or from about 20% to about 80%, by weight of theoral care composition.

Surfactants

The oral care composition can comprise one or more surfactants. Thesurfactants can be used to make the compositions more cosmeticallyacceptable. The surfactant is preferably a detersive material whichimparts to the composition detersive and foaming properties. Suitablesurfactants are safe and effective amounts of anionic, cationic,nonionic, zwitterionic, amphoteric and betaine surfactants.

Suitable anionic surfactants include, for example, the water solublesalts of alkyl sulfates having from 8 to 20 carbon atoms in the alkylradical and the water-soluble salts of sulfonated monoglycerides offatty acids having from 8 to 20 carbon atoms. Sodium lauryl sulfate(SLS) and sodium coconut monoglyceride sulfonates are examples ofanionic surfactants of this type. Other suitable anionic surfactantsinclude sarcosinates, such as sodium lauroyl sarcosinate, taurates,sodium lauryl sulfoacetate, sodium lauroyl isethionate, sodium laurethcarboxylate, and sodium dodecyl benzene sulfonate. Combinations ofanionic surfactants can also be employed.

Another suitable class of anionic surfactants are alkyl phosphates. Thesurface active organophosphate agents can have a strong affinity forenamel surface and have sufficient surface binding propensity to desorbpellicle proteins and remain affixed to enamel surfaces. Suitableexamples of organophosphate compounds include mono-, di- or triestersrepresented by the general structure below wherein Z₁, Z₂, or Z₃ may beidentical or different with at least one being an organic moiety. Z₁,Z₂, or Z₃ can be selected from linear or branched, alkyl or alkenylgroup of from 1 to 22 carbon atoms, optionally substituted by one ormore phosphate groups; alkoxylated alkyl or alkenyl, (poly)saccharide,polyol or polyether group.

Some other agents include alkyl or alkenyl phosphate esters representedby the following structure:

wherein R₁ represents a linear or branched, alkyl or alkenyl group offrom 6 to 22 carbon atoms, optionally substituted by one or morephosphate groups; n and m, are individually and separately, 2 to 4, anda and b, individually and separately, are 0 to 20; Z and Z may beidentical or different, each represents hydrogen, alkali metal,ammonium, protonated alkyl amine or protonated functional alkylamine,such as analkanolamine, or a R—(OCH2)(OCH)-group. Examples of suitableagents include alkyl and alkyl (poly)alkoxy phosphates such as laurylphosphate; PPGS ceteareth-10 phosphate; laureth-1 phosphate; laureth-3phosphate; laureth-9 phosphate; trilaureth-4 phosphate; C₁₂₋₁₈ PEG 9phosphate: and sodium dilaureth-10 phosphate. The alkyl phosphate can bepolymeric. Examples of polymeric alkyl phosphates include thosecontaining repeating alkoxy groups as the polymeric portion, inparticular 3 or more ethoxy, propoxy isopropoxy or butoxy groups.

Other suitable anionic surfactants are sarcosinates, isethionates andtaurates, especially their alkali metal or ammonium salts. Examplesinclude: lauroyl sarcosinate, myristoyl sarcosinate, palmitoylsarcosinate, stearoyl sarcosinate oleoyl sarcosinate, or combinationsthereof.

Other suitable anionic surfactants include sodium or potassium alkylsulfates, such as sodium lauryl sulfate, acyl isethionates, acyl methylisethionates, alkyl ether carboxylates, acyl alaninates, acyl gulatames,acyl glycinates, acyl sarconsinates, sodium methyl acyl taurates, sodiumlaureth sulfosuccinates, alpha olefin sulfonates, alkyl benzesulfonates, sodium lauroyl lactylate, sodium laurylglucosideshydroxypropyl sulfonate, and/or combinations.

Zwitterionic or amphoteric surfactants useful herein include derivativesof aliphatic quaternary ammonium, phosphonium, and Sulfonium compounds,in which the aliphatic radicals can be straight chain or branched, andone of the aliphatic substituents contains from 8 to 18 carbon atoms andone contains an anionic water-solubilizing group, e.g., carboxy,sulfonate, sulfate, phosphate or phosphonate. Suitable betainesurfactants are disclosed in U.S. Pat. No. 5,180,577. Typical alkyldimethyl betaines include decyl betaine or2-(N-decyl-N,N-dimethylammonio) acetate, coco-betaine or2-(N-coco-N,N-dimethyl ammonio)acetate, myristyl betaine, palmitylbetaine, lauryl betaine, cetyl betaine, cetyl betaine, stearyl betaine,etc. The amidobetaines can be exemplified by cocoamidoethyl betaine,cocoamidopropyl betaine (CADB), and lauramidopropyl betaine. Othersuitable amphoteric surfactants include betaines, sultaines, sodiumlaurylamphoacetates, alkylamphodiacetates, and/or combinations thereof.

Cationic surfactants useful in the present invention include, forexample, derivatives of quaternary ammonium compounds having one longalkyl chain containing from 8 to 18 carbon atoms such as lauryltrimethylammonium chloride; cetyl pyridinium chloride; cetyltrimethyl-ammonium bromide; cetyl pyridinium fluoride or combinationsthereof.

Nonionic surfactants that can be used in the compositions of the presentinvention include, for example, compounds produced by the condensationof alkylene oxide groups (hydrophilic in nature) with an organichydrophobic compound which may be aliphatic or alkylaromatic in nature.Examples of suitable nonionic surfactants can include the Pluronics®which are poloxamers, polyethylene oxide condensates of alkyl phenols,products derived from the condensation of ethylene oxide with thereaction product of propylene oxide and ethylene diamine, ethylene oxidecondensates of aliphatic alcohols, long chain tertiary amine oxides,long chain tertiary phosphine oxides, long chain dialkyl sulfoxides andcombinations of such materials. Other suitable non-ionic surfactantsincludes alkyl glucamides, alkyl glucosides, and/or combinationsthereof.

The one or more surfactants can also include one or more natural and/ornaturally derived surfactants. Natural surfactants can includesurfactants that are derived from natural products and/or surfactantsthat are minimally or not processed. Natural surfactants can includehydrogenated, non-hydrogenated, or partially hydrogenated vegetableoils, olus oil, passiflora incarnata oil, candelilla cera,coco-caprylate, caprate, dicaprylyl ether, lauryl alcohol, myristylmyristate, dicaprylyl ether, caprylic acid, caprylic ester, octyldecanoate, octyl octanoate, undecane, tridecane, decyl oleate, oleicacid decylester, cetyl palmitate, stearic acid, palmitic acid, glycerylstearate, hydrogenated, non-hydrogenated, or partially hydrogenatedvegetable glycerides, Polyglyceryl-2 dipolyhydroxystearate, cetearylalcohol, sucrose polystearate, glycerin, octadodecanol, hydrolyzed,partially hydrolyzed, or non-hydrolyzed vegetable protein, hydrolyzed,partially hydrolyzed, or non-hydrolyzed wheat protein hydrolysate,polyglyceryl-3 diisostearate, glyceryl oleate, myristyl alcohol, cetylalcohol, sodium cetearyl sulfate, cetearyl alcohol, glyceryl laurate,capric triglyceride, coco-glycerides, lectithin, dicaprylyl ether,xanthan gum, sodium coco-sulfate, ammonium lauryl sulfate, sodium cocoylsulfate, sodium cocoyl glutamate, polyalkylglucosides, such as decylglucoside, cetearyl glucoside, cetyl stearyl polyglucoside,coco-glucoside, and lauryl glucoside, and/or combinations thereof.Natural surfactants can include any of the Natrue ingredients marketedby BASF, such as, for example, CegeSoft®, Cetiol®, Cutina®, Dehymuls®,Emulgade®, Emulgin®, Eutanol®, Gluadin®, Lameform®, LameSoft®, Lanette®,Monomuls®, Myritol®, Plantacare®, Plantaquat®, Platasil®, Rheocare®,Sulfopon®, Texapon®, and/or combinations thereof.

Other specific examples of surfactants include sodium lauryl sulfate,sodium lauryl isethionate, sodium lauroyl methyl isethionate, sodiumcocoyl glutamate, sodium dodecyl benzene sulfonate, alkali metal orammonium salts of lauroyl sarcosinate, myristoyl sarcosinate, palmitoylsarcosinate, stearoyl sarcosinate and oleoyl sarcosinate,polyoxyethylene sorbitan monostearate, isostearate and laurate, sodiumlauryl sulfoacetate, N-lauroyl sarcosine, the sodium, potassium, andethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine,polyethylene oxide condensates of alkyl phenols, cocoamidopropylbetaine, lauramidopropyl betaine, palmityl betaine, sodium cocoylglutamate, and the like. Additional surfactants desired include fattyacid salts of glutamate, alkyl glucoside, salts of taurates, betaines,caprylates, and/or mixtures thereof. The oral care composition can alsobe sulfate free.

The oral care composition can comprise one or more surfactants each at alevel from about 0.01% to about 15%, from about 0.3% to about 10%, orfrom about 0.3% to about 2.5%, by weight of the oral care composition.

Thickening Agents

The oral care composition can comprise one or more thickening agents.Thickening agents can be useful in the oral care compositions to providea gelatinous structure that stabilizes the dentifrice and/or toothpasteagainst phase separation. Suitable thickening agents includepolysaccharides, polymers, and/or silica thickeners.

The thickening agent can comprise one or more polysaccharides. Somenon-limiting examples of polysaccharides include starch; glycerite ofstarch; gums such as gum karaya (sterculia gum), gum tragacanth, gumarabic, gum ghatti, gum acacia, xanthan gum, guar gum and cellulose gum;magnesium aluminum silicate (Veegum); carrageenan; sodium alginate;agar-agar; pectin; gelatin; cellulose compounds such as cellulose,microcrystalline cellulose, carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose,hydroxymethyl carboxypropyl cellulose, methyl cellulose, ethylcellulose, and sulfated cellulose; natural and synthetic clays such ashectorite clays; and mixtures thereof.

Other polysaccharides that are suitable for use herein includecarageenans, gellan gum, locust bean gum, xanthan gum, carbomers,poloxamers, modified cellulose, and mixtures thereof. Carageenan is apolysaccharide derived from seaweed. There are several types ofcarageenan that may be distinguished by their seaweed source and/or bytheir degree of and position of sulfation. The thickening agent cancomprise kappa carageenans, modified kappa carageenans, iotacarageenans, modified iota carageenans, lambda carrageenan, and mixturesthereof. Carageenans suitable for use herein include those commerciallyavailable from the FMC Company under the series designation “Viscarin,”including but not limited to Viscarin TP 329, Viscarin TP 388, andViscarin TP 389.

The thickening agent can comprise one or more polymers. The polymer canbe a polyethylene glycol (PEG), a polyvinylpyrrolidone (PVP),polyacrylic acid, a polymer derived from at least one acrylic acidmonomer, a copolymer of maleic anhydride and methyl vinyl ether, acrosslinked polyacrylic acid polymer, of various weight percentages ofthe oral care composition as well as various ranges of average molecularranges. Alternatively, the oral care composition can be free of,essentially free of, or substantially free of a copolymer of maleicanhydride and methyl vinyl ether.

The thickening agent can comprise one or more inorganic thickeningagents. Some non-limiting examples of suitable inorganic thickeningagents include colloidal magnesium aluminum silicate, silica thickeners.Useful silica thickeners include, for example, include, as anon-limiting example, an amorphous precipitated silica such as ZEODENT®165 silica. Other non-limiting silica thickeners include ZEODENT® 153,163, and 167, and ZEOFREE® 177 and 265 silica products, all availablefrom Evonik Corporation, and AEROSIL® fumed silicas.

The oral care composition can comprise from 0.01% to about 15%, from0.1% to about 10%, from about 0.2% to about 5%, or from about 0.5% toabout 2% of one or more thickening agents.

Prenylated Flavonoids

The oral care composition of the present invention can compriseprenylated flavonoid. Flavonoids are a group of natural substances foundin a wide range of fruits, vegetables, grains, bark, roots, stems,flowers, tea, and wine. Flavonoids can have a variety of beneficialeffects on health, such as antioxidative, anti-inflammatory,antimutagenic, anticarcinogenic, and antibacterial benefits.

Prenylated flavonoids are flavonoids that include at least one prenylfunctional group (3-methylbut-2-en- 1-yl, as shown in Formula VIII),which has been previously identified to facilitate attachment to cellmembranes. Thus, while not wishing to being bound by theory, it isbelieved that the addition of a prenyl group, i.e. prenylation, to aflavonoid can increase the activity of the original flavonoid byincreasing the lipophilicity of the parent molecule and improving thepenetration of the prenylated molecule into the bacterial cell membrane.Increasing the lipophilicity to increase penetration into the cellmembrane can be a double-edged sword because the prenylated flavonoidwill tend towards insolubility at high Log P values (highlipophilicity). Log P can be an important indicator of antibacterialefficacy.

As such, the term prenylated flavonoids can include flavonoids foundnaturally with one or more prenyl functional groups, flavonoids with asynthetically added prenyl functional group, and/or prenylatedflavonoids with additional prenyl functional groups synthetically added.

Other suitable functionalities of the parent molecule that improve thestructure-activity relationship (e.g,. structure-MIC relationship) ofthe prenylated molecule include additional heterocycles containingnitrogen or oxygen, alkylamino chains, or alkyl chains substituted ontoone or more of the aromatic rings of the parent flavonoid.

Flavonoids can have a 15-carbon skeleton with at least two phenyl ringsand at least one heterocyclic ring. Some suitable flavonoid backbonescan be shown in Formula IX (flavone backbone), Formula X (isoflavanbackbone), and/or Formula XI (neoflavonoid backbone).

Other suitable subgroups of flavonoids include anthocyanidins,anthoxanthins, flavanones, flavanonols, flavans, isoflavonoids,chalcones and/or combinations thereof.

Prenylated flavonoids can include naturally isolated prenylatedflavonoids or naturally isolated flavonoids that are syntheticallyaltered to add one or more prenyl functional groups through a variety ofsynthetic processes that would be known to a person of ordinary skill inthe art of synthetic organic chemistry.

Other suitable prenylated flavonoids can include Bavachalcone, Bavachin,Bavachinin, Corylifol A, Epimedin A, Epimedin Al, Epimedin B, EpimedinC, Icariin, Icariside I, Icariside II,

Icaritin, Isobavachalcone, Isoxanthohumol, Neobavaisoflavone,6-Prenylnaringenin, 8-Prenylnaringenin, Sophoraflavanone G,(−)-Sophoranone, Xanthohumol, Quercetin, Macelignan, Kuraridin,Kurarinone, Kuwanon G, Kuwanon C, Panduratin A, 6-geranylnaringenin,Australone A, 6,8-Diprenyleriodictyol, dorsmanin C, dorsmanin F,8-Prenylkaempferol, 7-O-Methylluteone, luteone, 6-prenylgenistein,isowighteone, lupiwighteone, and/or combinations thereof. Other suitableprenylated flavonoids include cannflavins, such as Cannflavin A,Cannflavin B, and/or Cannflavin C.

Preferably, the prenylated flavonoid has a high probability of having anMIC of less than about 25 ppm for S. aureus, a gram-positive bacterium.Suitable prenylated flavonoids include Bavachin, Bavachinin, CorylifolA, Icaritin, Isoxanthohumol, Neobavaisoflavone, 6-Prenylnaringenin,8-Prenylnaringenin, Sophoraflavanone G, (−)-Sophoranone, Kurarinone,Kuwanon C, Panduratin A, and/or combinations thereof.

Preferably, the prenylated flavonoid has a high probability of having anMIC of less than about 25 ppm for E. coli, a gram-negative bacterium.Suitable prenylated flavonoids include Bavachinin, Isoxanthohumol,8-Prenylnaringenin, Sophoraflavanone G, Kurarinone, Panduratin A, and/orcombinations thereof.

Approximately 1000 prenylated flavonoids have been identified fromplants. According to the number of prenylated flavonoids reportedbefore, prenylated flavonones is the most common subclass and prenylatedflavanols is the rarest sub-class. Even though natural prenylatedflavonoids have been detected to have diversely structuralcharacteristics, they have a narrow distribution in plants, which aredifferent to the parent flavonoids as they are present almost in allplants. Most of prenylated flavonoids are found in the followingfamilies, including Cannabaceae, Guttiferae, Leguminosae, Moraceae,Rutaceae and Umbelliferae. Leguminosae and Moraceae, due to theirconsumption as fruits and vegetables, are the most frequentlyinvestigated families and many novel prenylated flavonoids have beenexplored. Humulus lupulus of the Cannabaceae include 8-prenylnaringeninand xanthohumol, which play an important role in the health benefits ofbeer.

The prenylated flavonoid can be incorporated through the hops extract,incorporated in a separately added extract, or added as a separatecomponent of the oral care compositions disclosed herein.

Other Ingredients

The oral care composition can comprise a variety of other ingredients,such as flavoring agents, sweeteners, colorants, preservatives,buffering agents, or other ingredients suitable for use in oral carecompositions, as described below.

Flavoring agents also can be added to the oral care composition.Suitable flavoring agents include oil of wintergreen, oil of peppermint,oil of spearmint, clove bud oil, menthol, anethole, methyl salicylate,eucalyptol, cassia, 1-menthyl acetate, sage, eugenol, parsley oil,oxanone, alpha-irisone, marjoram, lemon, orange, propenyl guaethol,cinnamon, vanillin, ethyl vanillin, heliotropine, 4-cis-heptenal,diacetyl, methyl-para-tert-butyl phenyl acetate, and mixtures thereof.Coolants may also be part of the flavor system. Preferred coolants inthe present compositions are the paramenthan carboxyamide agents such asN-ethyl-p-menthan-3-carboxamide (known commercially as “WS-3”) orN-(Ethoxycarbonylmethyl)-3-p-menthanecarboxamide (known commercially as“WS-5”), and mixtures thereof. A flavor system is generally used in thecompositions at levels of from about 0.001% to about 5%, by weight ofthe oral care composition. These flavoring agents generally comprisemixtures of aldehydes, ketones, esters, phenols, acids, and aliphatic,aromatic and other alcohols.

Sweeteners can be added to the oral care composition to impart apleasing taste to the product. Suitable sweeteners include saccharin (assodium, potassium or calcium saccharin), cyclamate (as a sodium,potassium or calcium salt), acesulfame-K, thaumatin, neohesperidindihydrochalcone, ammoniated glycyrrhizin, dextrose, levulose, sucrose,mannose, sucralose, stevia, and glucose.

Colorants can be added to improve the aesthetic appearance of theproduct. Suitable colorants include without limitation those colorantsapproved by appropriate regulatory bodies such as the FDA and thoselisted in the European Food and Pharmaceutical Directives and includepigments, such as TiO₂, and colors such as FD&C and D&C dyes.

Preservatives also can be added to the oral care compositions to preventbacterial growth. Suitable preservatives approved for use in oralcompositions such as methylparaben, propylparaben, benzoic acid, andsodium benzoate can be added in safe and effective amounts.

Titanium dioxide may also be added to the present composition. Titaniumdioxide is a white powder which adds opacity to the compositions.Titanium dioxide generally comprises from about 0.25% to about 5%, byweight of the oral care composition.

Other ingredients can be used in the oral care composition, such asdesensitizing agents, healing agents, other caries preventative agents,chelating/sequestering agents, vitamins, amino acids, proteins, otheranti-plaque/anti-calculus agents, opacifiers, antibiotics, anti-enzymes,enzymes, pH control agents, oxidizing agents, antioxidants, and thelike.

EXAMPLES

The invention is further illustrated by the following examples, whichare not to be construed in any way as imposing limitations to the scopeof this invention. Various other aspects, modifications, and equivalentsthereof which, after reading the description herein, may suggestthemselves to one of ordinary skill in the art without departing fromthe spirit of the present invention or the scope of the appended claims.

Experimental Methods Acid Production and Acid Inhibition [%]

Acid production and acid inhibition were determined with the in vitroplaque glycolysis model (iPGRM). The purpose of this technique is toprovide a simple and quick method for determining if compounds have aninfluence on the metabolic pathways that plaque microorganisms utilizeto produce toxins that adversely affect gingival health.

The in vitro plaque glycolysis model (iPGRM) is a technique in whichplaque is grown from human saliva and treated with various agents todetermine anti-glycolytic activity of treatments. When bacteria convertsugar into energy with the help of enzymes, acids are formed. Theseacids demineralize and damage the dental enamel. The purpose of thistechnique is to provide a simple and quick method for determining iftreatment compounds have an inhibitory effect on the metabolic pathwaysthat plaque microorganisms utilize for the production of acids or toxinsand/or inhibit their growth. For the purposes of the work here, if thetest therapeutic compositions contain Sn, the Sn placebo should betested. Additionally, the antibacterial composition should be testedwith respect to its placebo to determine the iPGRM value for theantibacterial composition only. This is important if buffers, e.g.,bicarbonate, orthophosphate, calcium carbonate, are present in thecomposition in addition to the antibacterial composition.

A plaque biofilm was grown on glass rods from fresh pooled human salivaand Trypticase Soy Broth (TSB) at 37° C. over 2 days by dipping glassrods into and out of media in a reciprocating motion. Treatments were 2minutes of dentifrice slurry in water (1:5) or diluted treatment inwater (1:5). After treatments, biofilms were incubated with TSB andsucrose until pH indicator showed a color change (˜6hrs). The pH of themedia solutions was then measured to determine the amount of glycolysisinhibition relative to a negative control.

On Day 1, new glass rods (5 mm×90 mm) were polished approximately 25 mmfrom the un-tapered end on a lathe with silicon carbide paper of 240,320, 400, and 600 grit used sequentially. After the initial polishing,the rods should be polished with 600 grit paper before each test. Afterpolishing, rods were stored until ready to run test. Enough rods shouldbe polished for a full rack of treatments. A rack can treat 12compositions with 4 replicates of each composition such that the rackhas 48 rods.

On Day 2, saliva was collected daily during the test from a panel of5-10 people by paraffin stimulation and was refrigerated at 4° C. untilit was needed throughout the day. Pool saliva carefully (do not pour inwax/mucus) and mix thoroughly before use. The rods were removed fromstorage, rinsed with deionized water to remove any sanding residue,disinfected in 70% ethanol/water solution, and were allowed to dry on asterile surface. Subsequently, the rods were loaded into a hanging rackof holders that were used to dip the rods continuously into media vialscontaining growth media. The rod heights were adjusted and each rod wassecured in place using a rubber o-ring. In the early afternoon, 7 mL ofgrowth media (160 g of a solution of 3% TSB with 3% sucrose was mixedwith 240 g pooled human saliva. This TSB/sucrose solution should besterilized by autoclave before combining with the pooled human saliva.)into media vials. The media vials were arranged under the hanging rodson a rack in an incubation oven. The incubator has been previouslymodified such that a dipping motor can dip the rods into the media vialssubmerging 1.5 cm of the rod into the growth media at a frequency of 1dip per minute without the rods touching the walls of the media vial.The rods were dipped overnight this way.

On Day 3, an enriched growth media was prepared (500 g of a solution of3% TSB and 10% sucrose was mixed with 33 g pooled human saliva. ThisTSB/sucrose solution should be sterilized by autoclave before combiningwith the pooled human saliva.). This enriched growth media was pipettedinto a new set of media vials (7 mL per vial) and was swapped for theovernight growth media from Day 1. The rods were dipped throughout theday in this enriched growth media for 5 hours at 37° C. in theincubation oven. At the end of the day, a new overnight growth media wasprepared (40 g of a solution of 3% TSB was mixed with 360 g pooled humansaliva and 0.5 g sucrose), pipetted into a new set of media vials, andswapped for the enriched growth media. The rods were dipped overnight inthe same fashion as on the first day.

On Day 4, a glycolysis media was prepared by combining 0.15 g TSB, 25 gsucrose, and 500 mL deionized water resulting in a solution of 0.03% TSBand 0.5% sucrose in water. This solution was mixed then sterilized in anautoclave. The pH was then adjusted to 6.5 using 0.1M HCl and pipettedinto new media vials (7 mL). Two extra vials were filled than wereneeded for the rack of rods as pH blanks. Two drops of chlorophenol redsolution were added to each of the 4 tubes that contained the negativecontrol (Crest Cavity Protection slurry). Three drops of bromocresolpurple solution were added to 2 tubes that contained the positivecontrol (1% Chlorhexidine solution). Set the rack aside until treatmentsare complete. Vials were prepared containing 12 mL of deionized water torinse off the treatments. Vials were prepared containing the treatmentslurries/solutions (7mL) of homogenized treatment and water. The rodswere dipped into the treatment vials for 2 minutes, rinsed for 10 dipsin a first set rinse vials, rinsed for 10 dips in a second set of rinsevials, rinsed for 10 dips in a third set of rinse vials, and returned tothe incubator rack. The entire biofilm was treated and rinsed. Once alltreatments were complete, the biofilms on the rods were fully submergedin the glycolysis media inside the incubation oven with no dipping for 2hours. After two hours, the dipping apparatus was activated. The totalincubation time was between 3 to 7 hours. Incubation is terminated whenthe pH value in the glycolysis media of the negative controls is between4.8-5.6, more ideally 4.9-5.2, and when the pH value in the glycolysismedia of the positive controls is above the negative control. If theindicator dye in the positive control turns yellow, i.e., the pH hasdropped beneath 5.2, the incubation has gone on too long and the testwill need to be repeated.

After incubation termination on Day 4, the rods were removed from theglycolysis media and allowed to dry in the oven. The glycolysis mediawas removed from the incubation oven, allowed to return to roomtemperature, and the pH was measured in each vial and the blank vials todetermine the average pH change of the media following treatment. Thechange in pH is determined with respect to the blank vials. If the finalpH of the blank is less than 6.6, the test needs to be repeated. If thedifference between the positive and negative control is not significantin a student's t-test, the test needs to be repeated. If the change inpH of the negative control with respect to the blank is less than 1, thetest needs to be repeated.

After the pH values of all the vials were measured, the ApH per vial wasdetermined by subtracting its pH from the average pH of the blanks. Theglycolysis inhibition efficacy is determined from the following formula.The average ApH of a treatment was determined by averaging the resultsfrom the four replicate vials per treatment.

$\begin{matrix}{{{Acid}\mspace{14mu} {Inhibition}\mspace{14mu} (\%)} = {{100} - {\left( \frac{Avg\Delta pH_{sample}}{Avg\Delta pH_{{neg}\mspace{11mu} {ctrl}}} \right) \times 100}}} & {{Formula}\mspace{14mu} 2}\end{matrix}$

If the efficacy of the positive control (1% Chlorhexidine solution) isnot between about 65% to about 85% with respect to the negative control(Crest Cavity Protection, Procter & Gamble, Cincinnati, OH), the testwas repeated.

Anticaries Activity

The test design used here is similar to those found in the FDA Method#37 of the Fluoride Anti-Caries OTC Monograph. The major variations arethe diet used (MIT 200 rather than #469), the caries score method (Keyesmethod rather than HMA), and treatment frequency. Experimentalprocedures were conducted according to the FDA regulations Part 58.

Using litters as a covariate, the use of between 50 and 58 (depending onthe type of fluoride) animals per treatment group satisfies the moststringent power requirements of the ADA' s Council on DentalTherapeutics 20% clinical difference between treatments at 80% power.However, we have been routinely using 40 animals per treatment group andboth the ADA's CDT and the FDA have consistently accepted these tests.This requires initiating the study with 40 animals per group.Twenty-three (23) litters provided these animals. When studies are sizedas such, treatment differences of approximately 16% have been found tobe significant on occasion, thus is generally considered the cusp ofclinical significance.

All protocols are reviewed and approved by the Institutional Animal Careand Use Committee prior to the receipt of animals.

The animals were weanling mixed-sex Sprague Dawley rats; weighing 29-53grams. Due to the shipping schedule of the supplier, the dams werereceived with their entire birth litter. The litters were received whenthe pups were 6 days of age and litter size was reduced at 8 days of ageto ten (10) pups per litter. Twenty-five (25) litters were purchased.The five extra litters were to allow for any mortality prior tostratification. Any unused animals were euthanized after the studystratification.

The litters were maintained in large solid-bottom (box-type) cages withdams until the pups were weaned at 18 days of age. Starting at 9 days ofpup age, the dams were rotated daily among the litters until the pupswere weaned at 18 days of age. The pups were maintained in the box cagesuntil 21 days of age. At that time, the pups were stratified and housedin pairs in suspended wire-bottomed cages that had been cleaned andsanitized prior to usage. The change in caging was required to preventartificially increasing the caries rate due to direct contact bedding.The cages were arranged so that all animals of the individual groupswere together and the cages were labeled with group designation andtreatment (treatment code) that the animals received.

When the pups were 21 days of age they were given unique numbers byear-punch with records kept of littermates. Animals were assigned togroups in such a manner that groups were balanced for litter, weight andsex. There were 40 animals per group.

Upon receipt, dams and litters were provided rodent lab diet until thepups were 8 days of age. On day 8 (pup age) dams and litters wereprovided Diet MIT 305. Pups were provided Diet MIT 200 ad libitum at day18 (pup age) and throughout the test period. All animals were providedwith deionized water ad libitum.

Box caging was changed at day 13 and again at day 18 of pup age.Following administration of the inoculum, box cages and the bedding weredecontaminated by autoclaving prior to sanitizing. Cage boards werechanged three times a week at the time when fresh food and water weregiven (Monday, Wednesday and Friday). Clean and sanitized water bottlesand food jars were provided weekly. Suspended caging and banks weresanitized bi-weekly. The animals were observed daily by a staff memberand weekly by the attending veterinarian for any signs of healthproblems. The animals were housed in an AAALAC-accredited facility. Roomtemperature was maintained at 72° F. (±6° F.) with 10-15 air changes perhour and a 12-hour light cycle.

On day 15 (pup age), the animals received an oral inoculation ofstreptomycin-resistant S. sobrinus 6715 (ATCC strain #27352) culture.This involved flooding the mouth with 0.2 ml of culture/animal. On day18 (pup age) the animals were inoculated with S. sobrinus for threeconsecutive days (age 18, 19 and 20 days). This involved placing 0.1 mlof the S. sobrinus culture on the occlusal surfaces of each of themandibular molar quadrants, putting 10 cc of this concentration-adjustedculture into each sanitized and filled water bottle, and lightlyspraying the bedding with no more than 10cc of the remaining culture.All water bottles were removed and sanitized 24 hours after inoculum hasbeen added. The inoculums were administered to the animals with a 200micropipette.

The treatment phase began at day 22 of pup age. Each treatment had alabeled plastic beaker that was designated for that treatment only.Fresh materials (i.e., obtained from the stock supply) were used foreach treatment. The dentifrices were mixed in a 1:1 ratio (by weight)with deionized water. Specifically, 10 grams of dentifrice was weighedinto a 30 ml beaker; 10 grams of deionized water was then added to thedentifrice. The mixture was then stirred by hand (30 seconds) with aclean micro spatula for the purpose of creating a smooth mixture. Thebeaker containing the slurry and a small magnetic stirring bar wasplaced on a magnetic stirrer, which was set at the lowest speed andallowed to stir for four (4) minutes prior to treatm4ent. The slurry wasprepared immediately prior to each treatment.

A cotton-tipped applicator was dipped into the slurry (for 2 seconds)and was applied to one-half of the rat's mouth in such a way that thesides of the applicator came into contact with both the mandibular andmaxillary molars on one side of the mouth. The treatment wasaccomplished by using a rolling motion of the sides of the applicatorover the mandibular and maxillary molar teeth for 15 seconds. Theapplicator was dipped into the slurry for the second time (again, for 2seconds) and the other side of the rat's mouth similarly treated for 15seconds. A new applicator was used for each animal.

Treatments were administered twice daily for five days with a singledaily treatment on weekends. The first treatment each day began atapproximately the same time every day, and the second treatment didbegin no earlier than six hours after the first treatment. Singulartreatments were given at a 24-hour interval on weekends. Treatmentmaterials were stored at room temperature. All treatment products werereturned to sponsor at study completion.

One week after the initiation of the inoculation regimen and at studytermination, an oral swabbing was taken from each rat using a sterilecotton swab (six-inch, single-tipped applicator). The microorganisms onthe mandibular and maxillary molar teeth were sampled, using a rollingmotion of the swab for 15 seconds on one side of the mouth, rolled overthe tongue, and rolled over the molar teeth on the other side of themouth for an additional 15 seconds. Immediately after the applicator wasremoved from the animal's mouth, it was streaked across half of a 100 mmpetri plate containing Mitis Salivarius agar to which 200 units/ml ofstreptomycin sulfate was added. The plates were incubated for 48 hoursat 37° C. with 10% CO₂. The colony count taken after the 48 hours ofincubation was recorded in the logbook.

The experimental duration of the rat caries studies was three weeks.Immediately prior to termination, all animals were observed for anyvisual signs of ill health or pathology, individually weighed and anoral swabbing taken to confirm S. sobrinus implantation. The animalswere euthanized by carbon dioxide inhalation. Code numbers were assignedto each animal and the heads were then removed, placed in individualjars along with the code number, and cooked under pressure (10 PSI for12 minutes). The hemijaws were then removed and freed of all softtissue.

The cleaned hemijaws (four quadrants) were put into plastic vials withthe code numbers taped to the vial. A murexide solution (0.3 g murexide;300 ml DI H2O and 700 ml of ethanol) was added to each vial and the jawswere allowed to stain overnight. The jaws were then rinsed and allowedto air dry.

The hemijaws were microscopically examined for smooth surface caries,sectioned, and then microscopically examined for sulcal andinterproximal caries using the Keyes Method. The scoring method isdetailed in Navia, JN, Animal Models in Dental Research, pp 287-290,1977; and Keyes, PH, J. Dent. Res. 37:1088-1099, 1958. All analyses wereperformed using SAS statistical software, version 9.4. The groups werecompared using analysis of variance (ANOVA), with a fixed effect forgroup and a random effect for litter. The litter effect was included inthe models to reduce a known factor affecting the variability of themeasurements. Pair-wise comparisons between groups were made usingTukey' s multiple comparisons procedure to control the overallsignificance level (α=0.05) of the comparisons.

The specific types of data, which were tabulated, and statisticallyanalyzed may include:

1) Mortality Data Experimental Phase

-   -   a. Initial number of animals    -   b. Final number of animals    -   c. Percent mortality

2) Growth Data Experimental Phase

-   -   a. Initial body weight (mean±S.E.M.) an ±Sb. Final body weight        (mean±S.E.M.)

3) Caries Experience

-   -   a. Enamel and dentinal involvement of smooth surface (buccal,        lingual) lesions (mean±S.E.M.)    -   b. Enamel and dentinal involvement of interproximal lesions        (mean±S.E.M.)    -   c. Enamel and dentinal involvement of total smooth surface        (buccal, lingual & interproximal) lesions (mean±S.E.M.) d.        Enamel and dentinal involvement of sulcal lesions (mean±S.E.M.)    -   e. Total caries involvement combining the scores from the Keyes        method of scoring smooth surface, interproximal, and sulcal        caries (mean±S.E.M.)

Preparation of Oral Care Compositions

The oral care compositions of TABLE 1A were prepared by combining one ormore humectants, water, sweetener(s), tin ion source, sodium gluconate,and/or flavor(s) to create a liquid mixture. The liquid mixture washomogenized at 25° C. for 2 minutes. Next, sodium hydroxide (50%solution) was added to the liquid mixture and the liquid mixture washomogenized at 25° C. for 2 minutes. A separate powder mixture wasprepared by combining a portion of the calcium ion source and anythickening agents, such as xanthan gum and/or sodiumcarboxymethylcellulose. The powder mixture was then combined with theliquid mixture. Next, the surfactant, such as sodium lauryl sulfate, wasadded to the mixture. The contents were homogenized at 25° C. for 2minutes. The hops extract was then combined with the mixture andhomogenized at 25° C. for 2 minutes. Finally, the remaining portion ofthe calcium ion source and the buffering agent were combined with themixture and homogenized at 25° C. for 2 minutes.

Preparation of Commercial Oral Care Compositions with Hops Beta Acid

The commercial oral care compositions were combined with hops beta acidextract or hops total extract by weighing out a portion of commercialoral care composition and mixing in the appropriate amount of hopsextract. The combined oral care composition was homogenized at 25° C.for at least 2 minutes.

TABLE 1A Oral Care Compositions Formula A Formula B Formula C Glycerin49.10 47.80 — Sorbitol — — 37.98 Water — — 13.00 SodiumMonofluorophosphate — 1.15 — Sodium Gluconate 1.00 1.00 1.00 SnCl₂ 1.101.10 1.10 CaCO₃ 32.00 32.00 32.00 Xanthan Gum 0.50 0.50 0.30Carboxymethylcellulose — — 1.00 Carbomer 1.00 1.00 — Sodium LaurylSulfate 1.40 1.40 1.29 Flavor 1.00 1.00 1.00 Sodium Saccharin 0.40 0.400.50 Stevia Glycosides 0.30 0.30 — Sodium Hydroxide 1.20 1.35 0.33 HopsBeta Acid Extract* 0.50 0.50 0.50 Sodium Bicarbonate 10.00 10.00 10.00Titanium Dioxide 0.50 0.50 — *Hops Beta Acid Extract supplied byHopsteiner ®, with 45% hops beta acids and less than 1% hops alpha acids

Formula A, B, and C, as shown in TABLE 1A, were prepared in accordancewith the Experimental Methods, described above. The Hops Beta Acids weresupplied by Hopsteiner® as an extract from Humulus lupulus. TheHopsteiner® extract was approximately 45%, by weight of the extract, ofhops beta acids and less than 1%, by weight of the extract, of hopsalpha acids. Formula A and B have hops beta acids with no independentlyadded water. Formula A and B differ only in that Formula B includes afluoride ion source (sodium monofluorophosphate, NaMFP), which was usedin the total enamel caries test shown in TABLE 4. Formula C include hopsbeta acids without fluoride in a high-water chassis.

TABLE 1B Hops Beta Acids Extract Specification Ingredient Amount (wt %)Hops Beta Acids 45 ± 2  Hops Alpha Acids 0.4 ± 0.3 Hops oils 1.5 ± 0.5Propylene Glycol 20 ± 15 Water <8% pH  11 ± 0.5

TABLE 1B describes the hops beta acid extract provided by Hopsteiner®.Since the hops beta acids are provided as an extract, there can be somevariability in the amounts of certain ingredients. However, the extractcomprises approximately 45%, by weight of the extract, of the hops betaacids and approximately 0.4%, by weight of the extract, of hops alphaacids. This is dramatically different to previous hops extracts whichtypically have more hops alpha acids than hops beta acids. Other minoringredients may be present in the Hops Beta Acid extract.

TABLE 2 Acid Production and Glycolysis Inhibition [%] after treatment of3-day biofilm Mean Acid Acid Production Inhibition (ΔpH) (%) TreatmentMean SE Mean SE Crest ® 1.55 0.027 3.43 1.68 Cavity Protection (NaF)Crest ® 0.91 0.038 43.14 2.39 Pro-Health ™ Advanced (SnF₂) Crest ® 0.510.025 68.49 1.55 Gum Care (SnF₂ + SnCl₂) 1% Chlorhexidine 0.4 0.01875.12 1.11 Formula A (Hops Beta Acids + SnCl₂) −0.05 0.022 102.96 1.34Formula C (Hops Beta Acids + SnCl₂) 0 0.013 100.08 0.79

TABLE 2 displays the change in acid production in a 3-day biofilm usingthe iPGRM test described herein. After treatment with a commercialCrest® toothpaste containing sodium fluoride, the acid product mean is1.55 with a mean inhibition of 3.43%. Treatment of the 3-day biofilmwith a Crest® toothpaste containing stannous fluoride resulted indecreases in acid production and a net mean acid inhibition of 43.14%(Crest® Pro-Health™) and 68.49% (Crest® Gum Care). This was an expectedresult as the stannous ion is known to act as an antibacterial, whichcan lower the number of bacteria producing acid in the biofilm. Crest®Gum Care performed slightly better than Crest® Pro-Health™ ^(TM) due toadditional amounts of stannous ions (i.e. SnCl₂). Chlorhexidine is anantibacterial agent that can be prescribed to treat gingivitis.Treatment with chlorhexidine resulted in a mean acid inhibition of75.12%, which was not unexpected because chlorhexidine is known as anextremely effective antibacterial agent.

TABLE 2 also shows that Formula A and C displayed essentially zero acidproduction with a mean acid inhibition of approximately 100%. It wasunexpected that Formula A and C (without a fluoride ion source) would beessentially 100% effective at preventing acid production without havingfluoride and/or chlorhexidine, two of the most prevalent and effectiveantibacterial agents.

TABLE 3 Total Enamel Caries Total % Positive % Negative Treatment EnamelCaries Control Control Silica Placebo^(a) 38.70 ± 2.06 47 0 Silica +NaMFP^(b) 31.55 ± 2.08 75 19 Crest ® Cavity 25.28 ± 1.99 100 35Protection^(c) Formula A 26.23 ± 2.01 96 32 ^(a)Silica placebo is thenegative control without any fluoride ion source ^(b)NaMFP at 1000 ppm^(c)NaF 1100 ppm + Silica is the positive control with silica and afluoride ion source

TABLE 3 displays the results from the rat caries test, FDA No. 37. Therat caries test a biological test method required by the U.S. FDAmonograph to show efficacy of an anticaries drug, currently includingonly fluoride ion sources. As shown in TABLE 3, the negative control,Silica Placebo, is a toothpaste with silica abrasive, but not anyfluoride ion source. Silica+NaMFP is a USP NaMFP toothpaste with sodiummonofluorophosphate and a silica abrasive. Crest® Cavity Protection is atoothpaste with sodium fluoride and a silica abrasive. In contrast,Formula A has no fluoride ion source or silica abrasive, but has hopsbeta acids and stannous chloride. Unexpectedly, Formula A (26.23),without any fluoride ion source, performed similar to the Crest® CavityProtection (25.28), a dentifrice with 1100 ppm sodium fluoride.Additionally, Formula A performed better than a dentifrice with sodiummonofluorophosphate with silica abrasive (26.23 for Formula A vs. 31.55for NaMFP). The only anticaries drugs listed in the U.S. FDA monographare stannous fluoride, sodium fluoride, and sodium monofluorophosphate.In other words, Formula A is a fluoride-free anticavity toothpaste.

TABLE 4 Final pH, Acid Production and Glycolysis Inhibition [%] aftertreatment of 3-day biofilm Acid Acid Production Inhibition (ΔpH) (%)Treatment Mean SD Mean SD Tom's of Maine Rapid Relief + 0.12 0.01 94.00.54 0.5 wt % Hops Beta Acid Tom's of Maine Rapid Relief + 1.69 0.0411.6 1.85 0.64 wt % Hops Total Tom's of Maine Rapid Relief (F Free) 1.730.01 9.8 0.62 Crest ® Pro-Health ™ Advanced (SnF₂) 1.42 0.04 25.6 2.06Crest ® Gum Care (SnF₂) 1.34 0.03 29.9 1.75 Crest ® Cavity Protection(NaF) 1.91 0.02 0.00 1.21

TABLE 4 shows that hops beta acid, can be added to fluoride-freetoothpaste and provide additional benefits, including toothpastes with avariety of active agents, abrasives, water levels, polyphosphate, etc.As shown in TABLE 4, the addition of hops beta acid improves theantibacterial performance of a fluoride-free oral care composition bythe iPGRM test method. Importantly, the antibacterial performance wasnot improved through the addition of a hops extract that included bothhops alpha acid and hops beta acid. In fact, the extract including bothhops alpha extract and hops beta extract, the “hops total extract,”decreased the antibacterial performance in many cases.

The hops beta extract used was the hops beta extract of TABLE 1B. Thehops total extract included hops alpha acid and hops beta acid. The HopsAlcohol-Free Liquid Extract (“hops total extract”) was purchased fromHawaii Pharm and used as is. Hops beta acid extract was added at 0.5 wt% and the hops total was added at 0.64 wt %. Different amounts of theextracts were used to balance the different concentrations of extractedhops acids in either composition. In all cases, the amount of hops acid(either hops alpha acid +hops beta acid or essentially solely hops betaacid) were essentially equivalent at approximately 0.23%.

For example, the hops beta acid extract and hops total extract wereadded to Tom's of Maine Rapid Relief, which was free of fluoride, butincluded arginine, calcium carbonate, and silica, as shown in TABLE 4.The addition of the hops beta acid extract to Tom's of Maine improvedthe acid inhibition from 9.8% to 94.0%. The addition of hops totalextract to Tom's of Maine only marginally increased the acid inhibitionfrom 9.8% to 11.6%.

In the other formulas where hops was added at this same level as thatused here (0.5 wt % solution), the average effect of the hops was anadditional 60% acid inhibition. However, in the Tom's of Maine RapidRelief formula with hops, the additional benefit was about 84%, a 25%increase in acid inhibition. The Tom's of Maine Rapid Relief formula hasthe basic amino acid, arginine. It is well known that arginolyticbacteria that can consume arginine would nevertheless prefer to consumesugar and make acid in the presence of a sugar source and at low pH,namely the conditions of the iPGRM used here. Therefore, in order forbacteria to effectively utilize arginine to produce ammonia andneutralize acid-forming biofilms, it is required that the biofilm pH bemaintained at quite a high level already. This tends to impedearginine's effectiveness in biofilms where sugar is present and the pHis low. As shown in TABLE 4, hops activates that arginolytic bacterialpathway by preventing the pH from falling in the presence of sugar.This, unexpectedly, produced a synergistic effect and resulted in a moreeffectively stabilized biofilm pH than either ingredient could achieveon its own.

Thus, hops beta acids are an extremely effective antibacterial agent,which can improve existing dentifrice formulations regardless ofchassis. Hops beta acids can improve antibacterial activity indentifrice compositions comprising sodium fluoride, sodiummonofluorophosphate, and/or stannous fluoride. Additionally, hops betaacid can improve antibacterial performance in dentifrice compositionsfree of fluoride. Hops beta acids can improve antibacterial activity indentifrice compositions that are anhydrous, low water, moderate water,or high water formulations. Hops beta acids can improve antibacterialactivity in dentifrice compositions comprising a silica abrasive and/ora calcium abrasive, such as calcium carbonate. Hops beta acids canimprove antibacterial activity in dentifrice compositions comprising abasic amino acid, such as arginine. Hops beta acids can improveantibacterial activity in dentifrice compositions comprising a tin ionsource, a zinc ion source, or combinations of tin and zinc ions.Importantly, these benefits were not found when a total extract (i.e.one with hops alpha acid and hops beta acid) was used.

Thus, described herein are oral care compositions with a mean acidinhibition of at least 50%, at least 55%, at least 60%, at least 70%, orat least 80%, upon the addition of hops beta acid, either through a hopsbeta acid extract, a direct addition of one or more hops beta acids, orany other suitable source of hops beta acid.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

Every document cited herein, including any cross referenced or relatedpatent or application and any patent application or patent to which thisapplication claims priority or benefit thereof, is hereby incorporatedherein by reference in its entirety unless expressly excluded orotherwise limited. The citation of any document is not an admission thatit is prior art with respect to any invention disclosed or claimedherein or that it alone, or in any combination with any other referenceor references, teaches, suggests or discloses any such invention.Further, to the extent that any meaning or definition of a term in thisdocument conflicts with any meaning or definition of the same term in adocument incorporated by reference, the meaning or definition assignedto that term in this document shall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. An oral care composition comprising: (a) fromabout 0.01% to about 10%, by weight of the composition, of hops betaacid; (b) abrasive; wherein the oral care composition is free offluoride.
 2. The oral care composition of claim 1, wherein the oral carecomposition is a toothpaste.
 3. The oral care composition of claim 1,wherein the oral care composition comprises from about 0.01% to about10%, by weight of the composition, of metal ion source.
 4. The oral carecomposition of claim 3, wherein the metal ion source comprises tin,zinc, or combinations thereof.
 5. The oral care composition of claim 4,wherein the tin comprises stannous chloride.
 6. The oral carecomposition of claim 1, wherein the hops beta acid comprises lupulone,colupulone, adlupulone, or combinations thereof.
 7. The oral carecomposition of claim 1, wherein the hops beta acid comprises onlynon-hydrogenated hops beta acid.
 8. The oral care composition of claim 1wherein the oral care composition comprises from about 10% to about 50%,by weight of the composition, of the abrasive.
 9. The oral carecomposition of claim 8, wherein the abrasive comprises calcium abrasive.10. The oral care composition of claim 9, wherein the calcium abrasivecomprises calcium carbonate.
 11. The oral care composition of claim 10,wherein the oral care composition is free of silica.
 12. The oral carecomposition of claim 1, wherein the oral care composition has an acidinhibition of at least 60% in the in vitro Plaque Glycolysis andRegrowth Model.
 13. The oral care composition of claim 1, wherein theoral care composition comprises from about 1% to about 20%, by weight ofthe composition, of buffering agent.
 14. An oral care compositioncomprising: (a) from about 0.01% to about 10%, by weight of thecomposition, of hops beta acid; and (b) from about 10% to about 50%, byweight of the composition, of calcium.
 15. The oral care composition ofclaim 14, wherein the oral care composition is free of silica.
 16. Theoral care composition of claim 14, wherein the oral care composition isfree of fluoride.
 17. The oral care composition of claim 14, wherein theoral care composition is a toothpaste.
 18. The oral care composition ofclaim 14, wherein the oral care composition comprises from about 0.01%to about 10%, by weight of the composition, of antibacterial agent. 19.The oral care composition of claim 18, wherein the antibacterial agentcomprises metal ion source.
 20. The oral care composition of claim 19,wherein the metal ion source comprises tin, zinc, or combinationsthereof.
 21. The oral care composition of claim 20, wherein the tincomprises stannous chloride.
 22. The oral care composition of claim 14,wherein the hops beta acid comprises lupulone, colupulone, adlupulone,or combinations thereof.
 23. The oral care composition of claim 14,wherein hops beta acid comprises only non-hydrogenated hops beta acid.24. The oral care composition of claim 14, wherein the calcium comprisescalcium abrasive, calcium salt, or combinations thereof.
 25. The oralcare composition of claim 24, wherein the calcium comprises calciumcarbonate.
 26. The oral care composition of claim 25, wherein the oralcare composition has a percent glycolysis inhibition of at least 60% inthe in vitro Plaque Glycolysis and Regrowth Model.
 27. The oral carecomposition of claim 14, wherein the oral care composition comprisesfrom about 1% to about 20%, by weight of the composition, of bufferingagent.
 28. An oral care composition comprising: (a) from about 0.01% toabout 10%, by weight of the composition, of antibacterial agent; (b)from about 10% to about 50%, by weight of the composition, of calcium,wherein the oral care composition is free of a silica abrasive and has apercent glycolysis inhibition of at least 60% in the in vitro PlaqueGlycolysis and Regrowth Model.
 29. The oral care composition of claim28, wherein the oral care composition is free of fluoride.
 30. The oralcare composition of claim 28, wherein the antibacterial agent compriseshops beta acid, a metal ion source, or combinations thereof.
 31. Theoral care composition of claim 28, wherein the antibacterial agentcomprises hops beta acid and a metal ion source.
 32. The oral carecomposition of claim 30, wherein the metal ion source comprises tin,zinc, or combinations thereof.
 33. The oral care composition of claim32, wherein the tin comprises stannous chloride.
 34. The oral carecomposition of claim 28, wherein the hops beta acid comprises lupulone,colupulone, adlupulone, or combinations thereof.
 35. The oral carecomposition of claim 28, wherein the hops beta acid comprises onlynon-hydrogenated hops beta acid.
 36. The oral care composition of claim35, wherein the oral care composition comprises from about 1% to about20%, by weight of the composition, of buffering agent.
 37. An oral carecomposition comprising: (a) from about 0.01% to about 10%, by weight ofthe composition, of hops beta acid; (b) from about 0.01% to about 10%,by weight of the composition, of metal ion source; (c) from about 10% toabout 50%, by weight of the composition, of calcium; and (d) from about1% to about 20%, by weight of the composition, of buffering agent,wherein the oral care composition is free of fluoride.
 38. An oral carecomposition comprising: (a) from about 0.01% to about 10%, by weight ofthe composition, of lupulone; (b) from about 0.01% to about 10%, byweight of the composition, of tin; (c) from about 10% to about 50%, byweight of the composition, of calcium carbonate; and (d) from about 1%to about 20%, by weight of the composition, of buffering agent, whereinthe oral care composition is free of fluoride.
 39. An oral carecomposition comprising: (a) from about 0.01% to about 10%, by weight ofthe composition, of hops beta acid; (b) from about 0.01% to about 10%,by weight of the composition, of stannous chloride; (c) from about 10%to about 50%, by weight of the composition, of calcium carbonate; and(d) from about 1% to about 20%, by weight of the composition, ofbuffering agent, wherein the oral care composition is free of fluoride.40. An oral care composition comprising: (a) from about 0.01% to about10%, by weight of the composition, of hops beta acid; and (b) from about0.01% to about 10%, by weight of the composition, of sweetener.
 41. Anoral care composition comprising: (a) from about 0.01% to about 10%, byweight of the composition, of hops beta acid; and (b) basic amino acid;wherein the oral care composition is free of fluoride.
 42. The oral carecomposition of claim 41, wherein the basic amino acid comprisesarginine, lysine, or combinations thereof.
 43. A method of preventingcaries on a tooth comprising contacting the tooth with a fluoride-freetoothpaste composition comprising hops beta acid.
 44. A method ofpreventing sugar acids in an oral cavity comprising contacting the oralcavity with a fluoride-free toothpaste composition comprising hops betaacid.
 45. A method of killing bacteria in an oral cavity with bacteriacomprising contacting the bacteria with a fluoride-free toothpastecomposition comprising hops beta acid.
 46. A method of disrupting abiofilm in an oral cavity comprising contacting the biofilm with afluoride-free toothpaste composition comprising hops beta acid.